The control of estrus cycle synchronization in animals is desirable for many reasons. The timing of fertility and mating in animals is influenced by many factors, such as puberty onset, seasonal conditions, diet, photoperiod, heat, stress, crowding, transportation, lactation, recovery from previous pregnancy, recovery from lactation, and a variety of hormonal, neuroendocrine and immunological factors. In farm animals, the ability to control the estrus cycle directly affects the efficiency of animal husbandry and the cost of animal products. Some domesticated animals, such as horses, are raised for racing and other competitive events. Race horses enter the racing season based on age. Animals born early in a year will be stronger and larger than horses born later in the season. What is needed is a method to control the estrous cycle in horses so that the timing of fertility may be selected.
At present, no approved product or procedure exists for efficient and precise estrus synchronization in swine within the United States. In Europe, feeding of an oral progestin sold under the trademark REGU-MATE (Roussell UCLAF, France), is approved for estrus synchronization in mature cycling pigs. The oral progestin simulates the presence of functional corpora lutea (CL) as if the pig were pregnant. REGU-MATE must be supplied daily in the feed for about two weeks to achieve estrus synchronization. REGU-MATE is also quite expensive at a cost of about $2 per day per animal. Removal of REGU-MATE following 11 to 14 days of feeding results in the resumption of synchronous estrus cycles. REGU-MATE is not currently approved for use in the United States.
In mature cycling gilts and sows, estrus may be synchronized by breeding followed later by termination of the pregnancy with exogenous prostaglandin (PG), such as PGF.sub.2 .alpha.. This is the so-called "breed to abort" strategy. Most commonly, this method is used to ensure full use of farrowing facilities. Producers usually breed more gilts and sows than will be required to fill the farrowing facilities for a particular farrowing group. Once enough females have remained pregnant through days 25 to 30 of gestation, the producer terminates the excess gilt pregnancies with PG to regress the CL, the progesterone secreting structure of the ovary. These females then return to estrus and are bred to fit into a subsequent farrowing group.
When producers select their own market weight gilts as replacement breeding stock, a degree of estrous synchronization can be obtained by keeping the selected gilts isolated from mature boars until they are to be introduced into the breeding herd. Gilts are then relocated to the breeding facilities and allowed contact with mature boars. Within two weeks of the initiation of relocation and boar exposure, 40 to 70% of gilts will experience their pubertal estrus. However, if gilts have already experienced puberty, they will not display estrus in a synchronous manner. The older and more reproductively competent gilts become, the more likely they are to respond to relocation and boar exposure. However, older gilts are also more likely to have experienced spontaneous puberty and thus, not be synchronized by movement and boar exposure. Therefore, a long felt and unfulfilled need of producers is to begin relocation and boar exposure to induce estrus when gilts are still prepubertal, but old enough to be near the time of puberty, i.e. peripubertal.
Producers can combine the movement and boar exposure strategy described above with the administration of a combination of pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG), sold under the name PG600 (Intervet, Inc., Millsboro, Del.), which is approved for use in swine. A high percentage of prepubertal gilts display estrus and ovulate following PG600 administration and boar exposure. Using PG600, producers can work with younger gilts, which are not as likely to have already experienced puberty. However, most producers prefer not to breed at the PG600-induced estrus due to a reduction in litter size in these gilts. Instead, producers wait and breed PG600-treated gilts at their second estrus. Unfortunately, many prepubertal gilts which are induced to display estrus and ovulate with PG600 fail to display subsequent estrus in a predictable manner. This variability increases production costs of raising pigs (feed costs, housing costs, breeding, etc.), thereby raising the price of meat and other products derived from swine. At present, swine producers have no good methods for synchronizing estrus and breeding in replacement females (gilts). What is needed is a tool that allows producers to group gilts to be bred and to reliably synchronize the occurrence of a highly fertile estrus. Such a method would decrease production costs, thereby decreasing the costs of meat and other products derived from pigs.
An additional problem for swine producers is that they often receive shipments of a number of replacement gilts sufficient to meet the breeding requirements of the next several weeks. These replacement gilts may come from the producer's own gilt multiplier herd or from a breeding stock company. If the gilts are near pubertal age at the time of receipt, the stress associated with shipping and mixing of these gilts often triggers pubertal estrus. The frequent result is that too many gilts are available for breeding during the first one to two weeks after receipt, while too few gilts are available three to four weeks after receipt. Variation in the age of the replacement gilts when they are received at the breeding facility adds to the difficulty. Between and within shipments, gilts may vary in age by two to three weeks. This variation in age produces a variable response of the gilts to boar exposure thereby increasing variation in the number of gilts available for breeding. At present, producers maintain a large pool of replacement gilts to ensure that a sufficient number of gilts will be available to meet their breeding targets. What is needed is a means to control estrus in a group of replacement gilts as they are received at the breeding facility. A method which would allow producers to reliably control the occurrence of a highly fertile estrus in gilts could potentially reduce the size of the gilt pool by 50%, resulting in savings in feed, facilities and labor.
A method of estrous synchronization would also be useful in sows. Following lactation, sows exhibit a degree of estrus synchronization, assuming that they are weaned after about day 17 of lactation and are in good body condition. Weaning removes the suckling-induced inhibition of pituitary gonadotropin secretion. The majority of sows display estrus within a week of the removal of the litter. However, many producers now employ early weaning strategies that wean the piglet from the dam as early as day 10 of age. While early weaning is good for the health of the piglets, this strategy increases stress on the sow, who has yet to recover from pregnancy and lactation, thereby causing variable return to estrus in sows following weaning from the litter. Accordingly, what is needed is a procedure which controls the return to estrus in sows following lactation. In early-weaned sows or in sows with poor body condition, it may be desirable to delay the return to estrus in order to allow the sow to recover from pregnancy and lactation.
Seasonal infertility in gilts and sows is another problem encountered by producers. Farrowing rates drop by 5 to 12% in females bred during the summer months (Love R. J., et al., 1993, J. Reprod. Fertil. (Suppl. 48):191-206). During this time, affected pigs fail to remain pregnant and they return to estrus within about 30 days of breeding. This is thought to be more an effect of long day lengths rather than of increased environmental temperatures, although both factors are involved. Data suggest that females bred during long days fail to recognize the pregnancy signals produced by the conceptuses on days 11 to 15 of pregnancy. Failure to recognize these signals results in loss of the pregnancy. What is needed is a way to mimic or augment the embryonic signals of pregnancy, thereby maintaining pregnancy in gilts and sows that are experiencing seasonal infertility.
In the pig, the CL must be maintained throughout the entire pregnancy or abortion results. PG can be administered at any time between days 14 and 90 of gestation with good return to estrus and good breeding success. However, many producers dislike using this methodology to synchronize estrus since an established pregnancy must be terminated. In order for the method to work, estrus must be detected, the female must be bred and she must become pregnant. What is needed is a method which is highly effective at producing synchronous estrous by inducing a pseudopregnancy, and does not involve breeding and abortion of an established pregnancy.
It has been known for many years that the life span of the pig CL can be extended by daily administration of high doses of estrogen (estradiol-17.beta., estradiol valerate or estradiol benzoate) on days 11 through 15 of the estrus cycle (Geisert R. D., et al., 1987, J. Reprod. Fertil. 79:163-172; Zavy, M. T., et al., 1988, Theriogenol. 30: 721-732; Guthrie, H. D. 1975, Theriogenol. 4:69-75; Pusateri, A. E. et al.,1996, Biol. Reprod. 55: 582-589). Days 11 through 15 of the estrous cycle are often referred to as the period of maternal recognition of pregnancy. On these days the pregnant pig receives embryonic hormonal signals, which maintain the CL and the pregnancy. If the dam does not receive these signals or if she does not recognize the pregnancy, her uterus secretes PG which destroys the CL, progesterone production ceases, and the pregnancy is lost. Very high doses of estrogen, injected intramuscularly on days 11 through 15 of the estrous cycle, are thought to mimic the embryonic signals produced during pregnancy and result in CL maintenance, i.e. pseudopregnancy. As a result of CL maintenance, serum progesterone concentrations remain elevated during pseudopregnancy. The CL in estrogen-induced, pseudopregnant pigs commonly persist for more than 60 days. However, the CL of pseudopregnant pigs remain sensitive to destruction by PG. Following PG administration, the CL die or regress and the pigs return to estrus within 3 to 7 days.
Fertility in gilts bred following an estrogen-induced pseudopregnancy has been reported to be very good (Zavy M. T., et al., 1988, Theriogenol. 30: 721-732; Guthrie, H. D. 1975, Theriogenol. 4:69-75). In fact, birth weights and postnatal survival were reportedly enhanced (Zavy M. T., et al., 1988, Theriogenol. 30: 721-732). Unfortunately, repeated administration of high dosages of estrogen poses additional health risks, such as cancer, to animals that receive estrogen and to the workers who administer estrogen. In addition, it is impractical and costly for swine producers to administer multiple injections of estrogen over a very narrow and specific number of days of the estrous cycle in order to induce pseudopregnancy. These methods, involving daily or repeated administration of estradiol, are impractical, labor intensive, and expensive to practice in large numbers of animals such as farm animals. In addition, such repeated administration of estradiol can be stressful to animals, thereby affecting reproduction and immunity. Producers of animals need more convenient and affordable methods to synchronize estrus cycles. What is needed is a simple and economical method for inducing pseudopregnancy in animals such as pigs, so that the CL of these pseudopregnant animals could be destroyed with PG, resulting in a predictable return to a highly fertile estrus.
In addition to estradiol, the compound zearalenone has been shown to extend the life span of the CL of the pig when fed. The fungus Fusarium Rosium, commonly found in moldy corn, produces zearalenone (Stob, M., et al., 1962, Nature 196:1318). Zearalenone has been demonstrated to have weak estrogenic properties (Lindsay, D. G. 1985, Fd. Chem. Toxic. 23: 767-774), possessing about 2% of the potency of estradiol-17.beta.. However, when administered orally in the pig, the liver metabolizes zearalenone to .alpha.-zearalenol which possesses about 20% of the potency of estradiol-17.beta.. Zeranol is a different compound from .alpha.-zearalenol. Zearalenone will extend the life span of the CL when fed to pigs at a dose of 7 to 20 mg/day during the time of maternal recognition of pregnancy, i.e., days 11 to 15 of the estrous cycle (Etienne, M. and Jemmali, M., 1982, J. Anim. Sci. 55: 1-10; Young, L. G. and King, G. J., 1986, J. Anim. Sci. 63: 1191-1196; Flowers, B., et al., 1987, J. Anim. Sci. 65: 1576-1584).
Accordingly, what is needed is a method to modulate and synchronize reproductive cycles in female animals, such as farm animals, and especially in pigs and horses. What is also needed is a method for inducing pseudopregnancy in animals, such as farm animals. Also needed is a method for maintaining the function of the CL and associated progesterone synthesis and/or secretion. This method should support uterine function thereby assisting in the maintenance of pregnancy. What is also needed is a method for controlling the timing of estrus and insemination in animals such as farm animals. Also needed is a method for facilitating controlled insertion of groups of prepubertal and peripubertal gilts into a breeding herd. A method for synchronization of estrus and breeding of sows following lactation is also needed. Also needed is a method for decreasing periods of infertility and returning animals to a fertile state. Such a method should decrease the costs of producing animals by decreasing the costs associated with prolonged housing, feeding, and unsuccessful attempts at reproduction, thereby reducing costs of products derived from animals.